Clinical presentation and management strategies for yolk sac tumor. A case series and review of the literature

Background: Yolk sac tumor (YST), also known as endodermal sinus tumor, is a highly malignant germ cell-derived tumor. As a rare disease, the diagnosis, prognostic factors, and optimal management of yolk sac tumor are difficult. The present study aims to investigate the clinicopathological features and optimal management strategies of yolk sac tumor. Results: We retrospectively investigated seventeen patients with yolk sac tumor in our institute between January 2010 to December 2019. The median age of the study population was 24 years (range 6–50 years). Most cases were female (11/17, 64.7%). Among the seventeen cases of YSTs, 8 cases were ovarian YSTs, 3 cases were mediastinum YSTs, 2 cases were testis YSTs. 94.1% patients had a markedly raised AFP. Surgery and chemotherapy were the main treatment methods for YST and improved the prognosis of patients. Conclusions: YST is a highly malignant and rare germ cell tumor, ovarian YST is the most common type. Early diagnosis and reasonable treatment can improve the prognosis of YST. These cases highlight the tumor’s characteristics. As more experience is gathered with this rare malignant tumor, the more likely we are to cure this disease.

sac tumors elsewhere, we know very little about their biological behavior and optimal treatment strategy.
In the present study, we retrospectively studied seventeen cases of YST from January 2010 to December 2019 treated in Henan Cancer Hospital, in an attempt to determine the common clinical features, prognosis and management strategies of this rare entity.

Patient and tumor characteristics
A total of seventeen patients were analyzed retrospectively. None of the patients had a previous history of malignant disease. The median age of the study population was 24 years (range 6-50 years). Most cases were female (11/17, 64.7%). Among the seventeen cases of YSTs, 8 cases were ovarian YSTs, 3 cases were mediastinum YSTs, 2 cases were testis YSTs. 94.1% patients had a markedly raised AFP. Clinicopathological features of patients were showed in Table 1. Some typical cases are described below. Clinicopathological features, treatment and follow up of the patients are discussed and summarized in Table 2.

Case 2
A 23-year-old woman with no significant past medical history was admitted to the hospital presented with a 7-days history of abdominal distension and found pelvic mass and ascites for 2 days. Physical examination can touch a solid mass of about 18 * 12 cm in size in the right accessory area. Imaging examination of CT suggests a huge mass in the right lower abdominal pelvic cavity, multiple metastatic nodules in ovarian and peritoneal, and massive peritoneal effusion (Fig. 1A).
Simultaneously the patient had a markedly raised AFP (> 1210 ng/mL). In order to confirm the diagnosis, the patient received laparoscopy plus pelvic tumor biopsy, after placement of the microscope, the pelvic peritoneal cavity had a light red bloody ascites of about 3000 ml. There were multiple white nodules on the peritoneal surface of the pelvic peritoneum, and a tumor of about 18*15*12 cm was seen on the right appendix. Biopsy pathology confirmed ovarian YST. The patient's clinical stage is too late to undergo surgery, two cycles of PEB combination preoperative chemotherapy was conducted. After 2 cycles, the original right lower abdominal pelvic mass was significantly smaller than before, the omentum was not thickened, and the peritoneal fluid disappeared. AFP declined to 38.03 ng/mL. Then, the patient underwent right ovariectomy and 4 cycles of adjuvant PEB combination chemotherapy. The patient was diagnosed and treated in 2013 and was alive without recurrence to now (Fig. 1B).

Case 3
A 31-year-old woman was admitted to the hospital presented with a 2-days history of ovarian mass.
The patient is special, because she was already 32 weeks pregnant. During the previous pregnancy physical examination, no abnormalities were found. Until 2 days ago, an ultrasound examination during pregnancy revealed an ovarian mass. Ultrasound examination shows that the ovarian mass is more likely to be malignant. Simultaneously the patient had a markedly raised AFP (> 1210 ng/mL).
After the treatment, the patient was regularly reviewed in our hospital, and since 2015, she was in stable condition with no signs of recurrence.

Case 4
A 50-year-old woman was admitted to the hospital presented with a 10-days history of pelvic mass.
This is a post-menopausal woman. The patient underwent an ultrasound examination at the local hospital 7 years ago, which revealed a pelvic mass. There was no discomfort symptom such as abdominal pain and bloating. She had not undergone treatment and had not been reviewed regularly.   (Fig. 2C).

Case 7
A 24-year-old man was admitted to the hospital presented with half a month history of dry cough. Half a month ago, the patient developed a dry cough without chest discomfort, chest pain, and other discomforts. He developed low fever at night, which can reach 38 ° C at high temperatures. Later, the patient's symptoms gradually worsened, and chest discomfort, asthma and other discomforts appeared. Chest CT revealed a huge mass in the anterior mediastinum of the chest, considering lung cancer. "Paclitaxel + carboplatin" was given for 1 cycle of chemotherapy. After coming to our hospital, a biopsy of the mediastinal mass was performed, and the pathology proved to be YST. CT showed an anterior mediastinal mass of 112*72 mm, multiple lymph nodes in the left clavicle and mediastinum, pleural effusion, multiple nodules in the lungs and liver, and metastases were possible, right brain metastasis with peripheral edema. Patients are generally in poor condition and cannot tolerate chemotherapy. Mediastinal masses and metastatic lesions progress rapidly in a month, followed by cerebral hemorrhage.

Case 8
A 28-year-old man was admitted to the hospital presented with half a month history of right testicle tumor. The patient had an enlarged right testicle 2 months ago, and later had back pain, intermittent fever, up to 39 ° C, night sweats, and MRI showed that the right testicle increased in volume with abnormal signal occupying, 29*18*34 mm in size. CT suggests multiple metastases in both lungs.
Then the patient underwent right testis and epididymis resection surgery, postoperative pathology showed: right testis YST. After surgery, the patient subsequently underwent 4 cycles of PEB combination chemotherapy. After chemotherapy, CT shows shrinkage of bilateral lung metastases, but the patient did not undergo maintenance chemotherapy. After half a year, both lung nodules increased compared to the previous, and multiple brain metastases appeared at the same time.
Later, the patient received Keytruda (Pembrolizumab) immunotherapy, liposomal doxorubicin, paclitaxel chemotherapy, cranial radiotherapy, and local interventional therapy. Despite multiple treatments were given, the treatment is not effective.

Discussion
YST, also known as endodermal sinus tumor, is a highly malignant and rare germ cell tumor, which was proposed by Teilum G in 1959 [3]. Ovarian YST is the most common type [4], 10-15% of cases may arise from various midline extragonadal sites. Between January 2010 to December 2019, only twenty-four cases of YSTs were diagnosed in our institute. It is because of the low incidence of YST, our understanding of the biological behavior of YST is not very well. In case 7, the patient was first diagnosed as lung cancer. So far, there is no large-scale review article in the database to discuss the biological behavior, treatment strategies, and prognosis of YST. Our present study retrospectively analyzed through a series of typical cases, in an attempt to determine the common clinical features, prognosis and management strategies of this rare entity.
Early diagnosis is of great significance for improving the treatment level of YSTs, but unfortunately, the clinical manifestations of YSTs lack specificity, and early stage patients generally have no obvious symptoms of discomfort. The main clinical symptom of YST is a huge mass, which is the same for YST of ovary and other sites [5]. In our present study, most patients present with massive pelvic, The cause of YST is still unknown, and traditional tumor risk factors, such as smoking, drinking, family history of the tumor, were not found in the above cases. In case 3, the patient had YST with concurrent pregnancy,during the previous pregnancy physical examination, no abnormalities were found, but at 32 weeks of pregnancy, the lesion was suddenly found. Whether pregnancy is the risk cause of YST is unclear. In general, the age of onset of YST is relatively young, the median age at the time of diagnosis of YST is 18 in the literature [6]. In case 1 of this present study, the youngest case was only 6 years old. Previous literature reports that postmenopausal women may also develop YSTs [7]. In case 4, the patient was a postmenopausal woman. The onset time of YST is unknown, when most patients are diagnosed, the tumor is already large. In case 4, the patient had found a pelvic tumor 7 years ago, in case 5, ultrasound examination revealed a left kidney cyst 8 years ago but was not treated. YST onset time may be relatively long, and regular physical examination is especially important for early detection of tumor.
Ultrasound, CT and MRI are the main imaging diagnosis methods of YST. YST imaging findings are lack of specificity. In the imaging examination, the YST has a variety of imaging manifestations. The inside of the lesion may be solid or mixed with cysts, and there may be bleeding in the cysts. Due to the abundance of tumor blood vessels, the solid components of the enhanced scan showed obvious uneven enhancement, and the delay period continued to strengthen. The characteristic manifestation of the disease was both cystic change and obvious enhancement [8][9][10]. A significant increase in AFP is a characteristic manifestation of the disease. After surgery and chemotherapy, a significant decrease in AFP indicates chemotherapy response and a good treatment effect, and elevation of AFP may indicate relapse or progression of disease. However, in case 5, the patient's AFP level has been within the normal range. Therefore, AFP levels may be normal in some patients.
Pathological diagnosis is the gold standard for diagnosis of YST, most cases were histologically diagnosed with YST after surgery. In case 7, imaging examinations showed multiple metastases, so a biopsy of the mediastinal mass was performed. Pathological diagnosis under light microscopy may not be sufficient, and in most cases require immunohistochemical examination to confirm the diagnosis [11]. Immunohistochemical staining of AFP is valuable for the histologic diagnosis of YST, newer markers for YST including glypican-3 and SALL-like protein 4 (SALL4) may be useful in the identification of the YST component histologically [12]. AFP and SALL4 were routinely tested and positive in above cases. The YST can be pure or mixed with other germ-cell or epithelial tumors, including endometrioid adenocarcinoma, embryonal carcinoma and so on [13,14]. Some cases in the present study were mixed germ cell tumors, partly yolk sac tumor and partly immature teratoma.
Mixed germ cell tumor (mainly composed of yolk sac tumor) was diagnosed in case 5.
Surgery and chemotherapy are the main treatment methods for YST. The ideal treatment mode of YST has been under exploration. The initial treatment method for YST of ovary is whole uterus plus double appendectomy and postoperative chemotherapy with a single alkylating agent, but the prognosis is still poor. Combined chemotherapy significantly improves the prognosis of YST, which also makes it possible to reduce the extent of surgery [15,16]. Local extended resection becomes the main surgical method in our present case series. Platinum-based combination chemotherapy regimen significantly reduces the risk of postoperative recurrence and improves patient's prognosis [17,18]. Previous literature reports that among cisplatin-including regimens, PEB is more effective than others [19].
Similar to previous reports, a chemotherapeutic regimen comprising taxanes and VP16 was also utilized in our cases [20]. In case 6, the patient did not receive any adjuvant chemotherapy and soon relapsed. For advanced cases, rescue and neoadjuvant chemotherapy is still an important treatment manner [21]. Previous literature reports that the recommended course of PEB chemotherapy is 4 cycles. In this study, most patients received 4-6 cycles of chemotherapy [5]. The optimal number of courses still needs to be explored. Whether immunotherapy is feasible still needs to be explored, such as case 8 who received PD1 immunotherapy after recurrence.
YST is a highly malignant tumor, but it can still obtain satisfactory prognosis if treated properly.
In our present study, the prognosis was good in most cases. Previous literature reports that the most common metastatic sites of YSTs are the lung and liver, once distant metastasis occurs, the disease progresses rapidly with a poor prognosis.

Conclusions
YST is a highly malignant and rare germ cell tumor, ovarian YST is the most common type. Surgery and chemotherapy are the main treatment methods for YST. Early diagnosis and reasonable treatment can improve the prognosis of YST. As more experience is gathered with this rare malignant tumor, the more likely we are to cure this disease.

Study setting and patients
Between January 2010 to December 2019, seventeen cases of YST were diagnosed and treated in Henan Cancer hospital with complete information. Inclusion criteria were pathological diagnosed cases of Yolk sac tumor, with complete clinical case data. In the seventeen cases of yolk sac tumors, three patients were histologically diagnosed with yolk sac tumor by core needle biopsy, then underwent extended resection and/or platinum-based chemotherapy. The other cases were histologically diagnosed with yolk sac tumor after surgery, and then underwent chemotherapy. We retrospectively reviewed the clinicopathological characteristic, treatment modalities and prognosis of these cases from medical records.